Blood glucose level is primarily determined by the balance between the uptake of glucose in peripheral tissues such as muscle and fat and the production of glucose in the liver. Insulin, which is secreted from the pancreas according to the blood glucose level, maintains homeostasis of blood glucose levels by promoting glucose uptake in these peripheral tissues and suppressing glucose production in the liver. When diabetes and so forth occurs caused by increased insulin resistance, the action of insulin weakens resulting in a disorder in the blood glucose level control function. As a result, a state of elevated blood glucose continues resulting in glucotoxicity throughout the body, and severe hyperglycemia causes diabetes complications such as retinopathy and neuropathy. Medicaments that enhance glucose uptake in peripheral tissues have the action of improving hyperglycemia by promoting glucose metabolism, and are useful for the treatment or prevention of diabetes, hyperglycemia, glucose intolerance, gestational diabetes mellitus or diabetes complications (Homko, C. J. et al., Diabetes, 2003, 52, 487-491; Giannoukakis, N. et al., Biodrugs, 2002, 16, 149-173).
A disease state associated with increased insulin resistance, or so-called insulin resistance syndrome, is the major cause of diabetes, while also being considered to be the fundamental cause of lifestyle diseases including circulatory diseases (arteriosclerosis, hypertension, etc.) and obesity (McVeigh, G. E. et al., Current Diabetes Reports, 2003, 3, 87-92; Chaudhuri, A. et al., Current Diabetes Reports, 2002, 2, 305-310; Sorisky, A. et al., American Journal of Therapeutics, 2002, 9, 516-521). Insulin resistance is related to glucose uptake in peripheral tissues, and improvement of insulin resistance is known to promote glucose uptake in peripheral tissues (Vazquez, M. et al., Methods & Findings in Experimental & Clinical Pharmacology, 2002, 24, 513-523). Thus, medicaments that enhance glucose uptake in peripheral tissues by acting on the function of insulin to improve insulin resistance are useful for the treatment or prevention of diabetes, hyperglycemia, glucose intolerance, gestational diabetes mellitus or diabetes complications caused by insulin resistance syndrome.
Although certain types of quinone compounds or nucleic acid derivatives have been known to demonstrate glucose uptake enhancing action in cells of peripheral tissues (for example, Zhang, B. et al., Science, 1999, 284, 974-977; Merill, G. F. et al., American Journal of Physiology, Endocrinology and Metabolism, 1997, 273, E1107-E1112, and so forth), HMG-CoA reductase inhibitors have not been known to demonstrate glucose uptake enhancing action on warm-blooded animal cells.
HMG-CoA (3-hydroxy-3-methylglutaryl-CoA) reductase inhibitors are well-known hyperlipemia therapeutic medicaments (for example, U.S. Pat. No. 4,346,227 et al.). Statins are typical HMG-CoA reductase inhibitors, and disease preventive effects in humans have been confirmed in various clinical studies. For example, pravastatin has been reported to demonstrate effects (preventive effects) that suppress the onset of arteriosclerosis, coronary artery disease and diabetes in a clinical study targeted at hyperlipemia patients (for example, MacMahon, S. et al., Circulation, 1998, 97, 1784-1790; Shepherd, J. et al., Lancet, 2002, 360, 1623-1630; Freeman, D. J. et al., Circulation, 2001, 103, 357-362; etc.).
However, HMG-CoA reductase inhibitors are not known to demonstrate therapeutic effects for diabetes, hyperglycemia, glucose intolerance or gestational diabetes mellitus as well as therapeutic or preventive effects for diabetes complications.